Treatment of iodine deficiency diseases

ABSTRACT

This invention relates to a composition for use in the treatment or prevention of iodine deficiency diseases or disorders such as fibrocystic dysplasia of the breast, breast cancer, endometriosis, ovarian cysts and premenstrual syndrome. More particularly, this invention relates to a composition for the treatment or prevention of iodine deficiency diseases or disorders, the composition comprising elemental iodine (I 2 ) which may also be referred to as metallic iodine or iodine metal. The elemental iodine can be used with any pharmaceutically acceptable carrier.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present patent application is a continuation-in-part application ofSer. No. 08/131,427, filed Oct. 4, 1993, now U.S. Pat. No. 5,389,385,which was a divisional application of Ser. No. 07/803,550, filed Dec. 9,1991, now U.S. Pat. No. 5,250,304, which was a divisional application ofSer. No. 07/292,968 filed Jan. 3, 1989, now U.S. Pat. No. 5,171,582,which was a continuation-in-part application of Ser. No. 06/889,947filed Jul. 28, 1986, now U.S. Pat. No. 4,816,255 which was acontinuation-in-part application of Ser. No. 06/760,950, filed Jul. 31,1985, now abandoned.

BACKGROUND OF THE INVENTION

The nomenclature of iodine deficiency breast syndrome has a varied pastwith Reclus in France, Schimmellbusch in Germany and Bloodgood in theUnited States contributing to the confusion. Pathological nomenclaturewas popular for a time with the terms fibroepitheliosis, fibroadenosisand epithelial adenosis reported in the literature. Recently, the mostcommon name applied seems to be fibrocystic disease. It is generallyagreed, that all of these terms, and several more, apply to an entitycharacterized by painful nodular breasts and supported pathologicallywith cystic spaces, epithelial hyperplasia or apocrine metaplasia andinteracinar fibrosis.

The etiology of the condition has remained obscure with various theoriesin ascendancy at any one time. These have included a prolonged lutealphase, a reversal of the estrone/estriol ratio, increased medianprolactin levels, or any upset in these complex interrelationships. Allof these etiological theories are supported by good research data. Morerecent suggestions have implicated caffeine in coffee, tea and chocolateusers and the increased estrogen intake in milk drinkers.

It is the inventors' position that there is a common denominator in allof these concepts and this is specific iodine ion deficient state. Inthis state, it is further postulated that the secreting cells of thebreast are sensitized to various stimuli to produce the changes noted.This sensitization can progress to overt malignancy if a carcinogen isadded to the rat model and possibly to the human female.

Clinically, the fibrocystic syndrome is the most common breast diseasethat affects North American women. The Cancer Committee of the AmericanAcademy of Pathology (1985) estimated the incidence at 50-80% of theadult female population.

Parallel findings indicate that at least fifty percent of all NorthAmerican and European women of child bearing age are suffering fromfibrocystic disease (fibrocystic dysplasia). Painful breasts are commonprior to the onset of menstruation and fibrocystic disease accentuatesthis tendency. Some women suffering from this disease have hard areas ofthickening with small pellet sized masses scattered throughout thebreast while other patients have marble sized cyst development.Fibrocystic disease of the breast affects one in two women between theages of 16 and 60.

The link between iodine deficiency states and an increased incidence ofbreast cancer is statistically valid on a geographical basis.Demographic evidence indicates that rates of morbidity and mortality dueto breast cancer are higher in areas of iodine inadequacy than inregions where iodine is readily available. Demographic surveys of Japanand Iceland show low incidences of endemic non-toxic goiter and breastcancer, while Mexico and Thailand show high incidences of goiter andbreast cancer. In addition, increased breast cancer in specificendemic-goiter regions in Poland, Switzerland, Australia, and the SovietUnion have been described in various publications. Similarly, in theUnited States and Canada iodine deficient regions (described by theWorld Health Organization) show a high census of breast disease.

The treatment of fibrocystic disease in the past has included neglect,hormonal manipulation with birth control pills, danazol (a masculinizinghormone), withdrawal of caffeine and cow's milk, or subcutaneousmastectomy. The treatment of this syndrome by a non-surgical techniquewith very low side effects would be more desirable and is offered bythis invention.

Previously, iodine, a trace element in the basic physiology of humans,has received much attention in its application to thyroid function. Thisled, in 1929, to the addition of potassium iodide to all salt sold inCanada. The addition resulted in a marked decrease in the iodinedeficiency disorders (I.D.D.) known as cretinism and endemic goiter.

Iodides and protein-bound iodines have been used to treat various otherhuman diseases, including hypercholesteremia, hyperlipemia, diabetes andtuberculosis. U.S. Pat. Nos. 4,187,294, 4,338,304 and 4,394,376, all toKamimae et al. disclose a composite containing a high amount ofprotein-bound iodine for the treatment of hypercholesteremia, diabetesand hyperlipemia, respectively. U.S. Pat. No. 4,259,322 to Lim disclosestuberculosis medication containing sodium iodide administered byintramuscular or intravenous injections.

Recent investigations have indicated that the iodine molecule isinvolved in the function of various organs in the body, including thesalivary glands, the stomach, the liver, the ovaries, endometrialtissues and the human female breast. Iodine deficiency appears to causean increase in carcinogenesis when a known breast carcinogen is given tosusceptible rats. In some studies, earlier onset of cancer is seen, andin others, a greater number of breast tumor sites and an increased sizeof tumor have been described.

Yunbing et al. related hyperplastic cystic disease of the breastetiologically to dysfunction of the ovaries with elevated estrogen levelcoupled with decreased progesterone level and abnormal reactivity ofbreast tissue to estrogen. Treatment of mammary dysplasia was directedto restoring normal ovarian function and hormonal balance of the gonadusing traditional Chinese medicines. These medicines include Sargassumwhich contains a high iodide concentration principally in the form ofpotassium iodide. Among those patients treated solely with traditionalmedicine, Yunbing et al. reported a cure rate of 65.4 percent. This ismuch below the rate quoted for this invention and not substantiated byanimal testing.

The first mention of the thyroid/iodine associated with the human femalebreast was made in 1896, by Dr. Beatson, who treated metastatic breastcancer, with some success, using desiccated thyroid in large doses.Desiccated thyroid contains an abundance of protein-bound iodine inaddition to the active hormone thyroxine.

Carcinoma of the breast is less prevalent in patients withhyperthyroidism than patients with hypothyroidism, and the survival ratein the former group is enhanced as compared to hypo or euthyroidpatients.

The first association of an iodine deficiency state and benign breastdysplasia was reported by Vishnyakova and Murivieva in 1966 from Russia.They reported a 71% improvement rate in women with dysplastic mastodyniatreated with potassium iodide (inorganic iodine).

Studies on rats have included iodine replacement therapy in animals madeiodine deficient by a Remington iodine-free diet. Employing iodideinorganic salts (sodium iodide) in food at both normal and excessivelevels as replacement, the breast dysplasia appeared to abate with apartial subsidence of epithelial hyperplasia and a loss of cystic spacesbut with a continuation of the fibrosis of the syndrome.

Laboratory support for the relationship of benign fibrocystic diseaseand iodine deficiency was furnished by Eskin reported in 1970 in theAnnals New York Academy of Science Journal, which is incorporated hereinby reference. Eskin was attempting to produce carcinoma in rat modelswith iodine deficiency, hypothyroidism, estrogen addition and acarcinogen. These laboratory studies were successful, but in thecellular steps to final neoplasia, microscopic changes resembling thoseof fibrocystic disease were produced. These changes included epithelialhyperplasia associated with mammary ducts and acinar cells, cystformation and an increase in interacinar fibrosis. All previous animalmodels produced with hormonal manipulation produced hyperplasia withsome cystic dilation but without the interacinar fibrosis that ischaracteristic of the human condition.

Other iodine-deficient disease states for which effective treatmentshave not been discovered include endometriosis and premenstrualsyndrome.

Endometriosis is characterized by hormonally responsive endometrialtissue implants in extra-uterine sites. The etiology of endometriosis isthought to be the transplantation of uterine lining cells through thefallopian tubes, the lymph channels and/or the blood stream to theabdominal cavity. Another suggested theory is that the peritoneumundergoes metaplasia to produce endometrial cells without direct accessto cellular transplants. The transplanted or transformed islands ofendometrial tissue act in a similar fashion to the uterine cells, withswelling and then bleeding at the time of menstruation.

Current treatment modalities for endometriosis are directed at thenormal fluctuations of the estrogen/ progesterone complex. Medicationsinclude birth control pills, masculinizing hormones such as danazol, orestrogen suppression drugs such as tamoxifen. In severe cases, totalabdominal hysterectomy is the only therapy that is effective. All of themedical therapies are anti-estrogen.

Premenstrual syndrome is defined as the cyclic recurrence in the lutealphase of the menstrual cycle of a combination of distressing physical,psychological and/or behavioral changes, of sufficient severity toresult in deterioration of interpersonal relationship and/orinterference with normal activities. The symptoms of premenstrualsyndrome include breast pain, swelling and tenderness, lower abdominalbloating, constipation, increased appetite with cravings for salt orchocolate, fatigue, emotional lability with temper tantrums, anger orcrying, depression, anxiety with tension, irritability with tendency toseek confrontations, aversion to sexual relations, insomnia, confusionand/or violence.

Although premenstrual syndrome has been classified as a psychiatricinstability in the premenstrual phase, psychiatric counselling has notproven to be an effective treatment. Other treatment modalities includeprogesterone administration, tranquilizers and pain control medication,surgical removal of the ovaries and naloxone administration. However,these other treatment modalities are also usually ineffective.

Other diseases or disorders, which are associated with increased ovarianfunction and/or estrogen production include breast cancer and ovariancysts.

The nomenclature of iodine-containing compositions is ambiguous, andoften misleading. Iodine is most often administered in an inorganiciodide form or as protein-bound iodine. Both of these forms utilize theI⁻ ion and are not elemental iodine (I₂).

However, in the literature, both of these forms have been referred to asiodine, which to the unskilled reader might connote the use of elementaliodine (I₂). Prior to its use by the current inventors, elemental iodine(I₂) in a pure solution has not been administered as a medicationspecifically to treat iodine deficiency states.

Elemental iodine in a suspension form (i.e. containing micro and macroparticles of iodine) has been used to treat thyroid conditions as taughtby Polley in U.S. Pat. No. 4,384,960. However, such a suspension is anundesirable form of iodine. The iodine particles cause the suspension tobe of unknown strength. Furthermore, the iodine particles cause theunwanted side effects of nausea, vomiting and diarrhea when thesuspension is administered to patients. The iodine particles are presentin the Polley suspension due to the method of manufacture whichcomprises direct exposure of iodine pellets, crystals or dust to waterthrough a porous container.

SUMMARY OF THE INVENTION

This invention relates to a composition comprising elemental iodine foruse in the treatment or prevention of an iodine-deficiency disease ordisorder in a mammalian patient. According to the present invention, theiodine deficiency disease or disorder is selected from the groupconsisting of fibrocystic dysplasia, breast cancer, endometriosis,premenstrual syndrome and ovarian cysts.

According to a further embodiment of the present invention, there isprovided a method for therapeutically treating or preventing an iodinedeficiency disease or disorder in a mammal in need thereof. Further,according to this embodiment of the present invention, there is provideda method for therapeutically treating or preventing an iodine deficiencydisease or disorder selected from the group consisting of fibrocysticdysplasia, breast cancer, endometriosis, ovarian cysts and premenstrualsyndrome, comprising administering to a mammal in need thereof asufficient amount of elemental iodine.

In a further embodiment of this invention, there is provided a methodfor therapeutically treating or preventing an iodine deficiency diseaseor disorder selected from the group consisting of fibrocystic dysplasia,breast cancer, endometriosis, ovarian cysts and premenstrual syndromecomprising administering to a mammal in need thereof from about 0.01 toabout 0.20 milligrams of elemental iodine per kilogram of body weight.

In a further embodiment of this invention, there is provided a methodfor therapeutically treating or preventing an iodine deficiency diseaseor disorder selected from the group consisting of fibrocystic dysplasia,breast cancer, endometriosis, ovarian cysts and premenstrual syndrome,comprising administering to a mammal in need thereof from about 0.03 toabout 0.16 milligrams of elemental iodine per kilogram body weight.

In a further embodiment of this invention, there is provided a methodfor therapeutically treating or preventing an iodine deficiency diseaseor disorder selected from the group consisting of fibrocystic dysplasia,breast cancer, endometriosis, ovarian cysts and premenstrual syndrome,comprising administering to a mammal in need thereof from about 1 toabout 20 of milligrams of elemental iodine per day.

In a further embodiment of this invention, there is provided a methodfor therapeutically treating or preventing an iodine deficiency diseaseor disorder selected from the group consisting of fibrocystic dysplasia,breast cancer, endometriosis, ovarian cysts and premenstrual syndrome,comprising administering to a mammal in need thereof from about 2 toabout 12 milligrams of elemental iodine per day.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 to 9 show phase-contrast photomicrographs of human or rat femalebreast tissue showing normal cell configuration or abnormal celldevelopment characteristic of fibrocystic disease:

FIG. 1 shows the breast tissue from a human female with fibrocysticdisease showing epithelial hyperplasia, cystic spaces and increasedfibrous tissue;

FIG. 2 shows breast tissue from a normal female rat showing normalcellular configuration;

FIG. 3 shows breast tissue from a female rat rendered iodine deficientshowing cystic spaces, epithelial hyperplasia associated with duct andacinar cells and increased fibrous tissues;

FIG. 4 shows breast tissue from a female rat on an iodine deficient dietwith estrogens added to the model;

FIG. 5 shows breast tissue from a female rat on a normal iodinecontaining diet with estrogens added;

FIG. 6 shows breast tissue from a female rat on an iodine deficient dietwith a carcinogen (dimethyl benzanthracene) added to the model therapythereby producing carcinoma;

FIG. 7 shows breast tissue from a female rat on an iodine deficient dietand then given sodium iodide as a replacement treatment;

FIG. 8 shows breast tissue from a female rat on an iodine deficient dietand then given Caseo Iodine (Iodaminol, Trade Mark of Desbergers Ltee,Montreal), as replacement treatment;

FIG. 9 shows breast tissue from a female rat on an iodine deficient dietand then given elemental iodine as replacement treatment;

FIG. 10 illustrates the solubility of iodine in water relating theconcentration of iodine as a function of temperature;

FIG. 11 illustrates the results of replacement therapy with caseoiodine;

FIG. 12 illustrates the characteristics of a study group treated withelemental iodine;

FIG. 13 illustrates a comparison of results of replacement therapy withcaseoiodine versus elemental iodine (Denovo Group);

FIG. 14 illustrates a comparison of results of replacement therapy withcaseoiodine versus elemental iodine (Transfer Group); and

FIG. 15 illustrates the various complications manifest in the Denovo andTransfer Groups subjected to elemental iodine therapy.

DETAILED DESCRIPTION OF THE INVENTION

A. Iodine Treatment of Fibrocystic Dysplasia

The present invention provides a method and composition for use in thetreatment or prevention or iodine deficiency diseases or disorderscomprising elemental iodine (I₂). The iodine deficiency diseases areselected from fibrocystic dysplasia, breast cancer, endometriosis,ovarian cysts or premenstrual syndrome.

In the treatment of fibrocystic dysplasia, the use of elemental iodineresults in not only the relief of pain associated with the disease, theregression of epithelia hyperplasia, and the dissipation of cysts, butadditionally the control and dissolution of the fibrous tissue.

The present invention further provides a method and composition for thetreatment or prophylaxis of breast cancer. Particularly, element iodine(I₂) interacts with breast estrogen receptors to reduce the prevalenceof breast cancer in susceptible mammals and halts neoplastic changes inmammals with malignant breast cancer.

The present invention further provides a method and composition for thetreatment of endometriosis. Particularly, elemental iodine (I₂)neutralizes the ovarian function and estrogen production to controlendometriosis and alleviate its symptoms.

In a further aspect of the present invention, a method and compositionfor the treatment of premenstrual syndrome is provided. Particularly,elemental iodine neutralizes the ovarian function and estrogenproduction to alleviate the symptoms of premenstrual syndrome.

The present invention is also directed to the treatment or prevention ofovarian cysts. Particularly, elemental iodine neutralizes the ovarianfunction and estrogen production to reduce or eliminate the occurrenceof ovarian cysts.

For the purpose of this application, elemental iodine refers to diatomiciodine (I₂) which may also be referred to as metallic iodine or iodinemetal. In an effort to overcome the disadvantages of the prior art, thepresent invention provides a pharmaceutically acceptable form ofelemental iodine, which may be administered orally, without the viletaste of previous replacement compositions, notably Lugol's iodine(potassium iodide in aqueous solution), and without the side effectsassociated with various prior art treatments. According to the presentinvention, elemental iodine can be admixed with a suitablepharmaceutical carrier for oral administration. The pharmaceuticalcarrier can be a solid carrier such as lactose, starch, sugar, gelatin,cellulose or other nonmedical ingredients, either alone or in mixturesthereof.

Thus, according to the present invention, elemental iodine is meant toinclude any pharmaceutically acceptable form of elemental iodine whichcan be administered orally.

Elemental iodine can also be prepared as an aqueous solution of I₂ inwater or other physiological aqueous vehicles. According to the presentinvention, elemental iodine in an aqueous solution is produced by aunique method which prevents any micro or macro particles of iodine frombeing present in the solution. Iodine crystals are placed in a sealedplastic bag or container which is exposed to water at about 20° C. Theiodine crystals sublime, and iodine vapor passes through the plastic andinto the water to produce a pure solution of elemental iodine withoutany particulate matter.

The particular plastic composition used must be penetrable by iodinevapor but impermeable to water and micro or macro particles of iodine.The inventors have found that suitable plastics include polyethylene,polypropylene, polybutylene and related plastic compositions. Apreferred plastic composition is a 1 millimeter thick film of linear,low density polyethylene.

The concentration of the pure solution after the iodine vapor has passedthrough the plastic to the water is about 270 milligrams elementaliodine per liter of solution to about 350 milligrams of elemental iodineper liter of solution. A preferred concentration is 300 mg of elementaliodine per liter of solution.

As stated above, the pure solution with the required concentration isobtained by exposing a plastic container of prilled iodine to water foran amount of time sufficient to yield a pure iodine solution with aconcentration of about 270 to about 350 milligrams elemental iodine perliter of solution. The temperature of the water effects the rate ofsublimation of the prilled iodine, and therefore effects the time tostabilization of the pure solution at the required concentration.Preferably, 7 grams of prilled iodine is placed in a polyethylenecontainer, and submerged in 100 ml of distilled water at about 20° C.for about 18 hours to produce a pure iodine solution having the requiredconcentration (about 270 to about 350 milligrams elemental iodine perliter of solution).

Alternatively, the polyethylene container with 7 grams of prilled iodineis submerged in 100 ml of distilled water at about 50° C. for about 30minutes to obtain the pure solution having the required concentration.At 50° C., the prilled iodine sublimes at a much faster rate.

Once the pure solution has been produced, it is an easy process for thepatient to replenish the solution after use. Refilling a partially useddispenser of the solution with distilled water at 20° C. results infurther sublimation of the prilled iodine in the polyethylene container,and stabilization of the solution at the required concentration occursin about 6 hours.

The pure elemental iodine solution produced by the above-describedmethods allows an accurate dosage regime to be maintained, and reducesthe unwanted side effects of nausea, vomiting and diarrhea. Both ofthese advantages are attributable to the lack of particulate iodine inthe solution.

Breast dysplasia and neoplasia are influenced by the available iodineion. Carcinogenesis occurs early in estrogen therapies in associationwith iodine deficiency.

The subsequent addition of iodine to iodine-deficient diets in ratexperiments reversed breast dysplasia. Once breast lesions wereestablished, only chronic iodine replacement manages the dysplasia thatis formed.

The first iodine product used in the reversal experiment was sodiumiodide. The use of sodium iodide resulted in reversal of thepathological changes to a degree with the partial subsidence of cystformation, epithelial hyperplasia and fibrosis. The interacinar fibrosisremained.

Iodine caseinate, an organified form of iodine was next tested based onthe proven ability of the breast tissue to deorganify iodine to secreteiodine as in organic potassium iodide in milk. The breasts' ability toorganify inorganic iodine with the addition of protein molecules, somein the form of thyroxin, was proven by Eskin and reported in "Iodine inBreast Cancer-A 1982 Update" in Biological Trace Element Research 538.

The testing of iodine caseinate on the rat model, which first began in1974, resulted in a reversal of the cyst formation and the epithelialhyperplasia. The interacinar fibrosis remained as a hallmark ofcontinuing pathology.

Iodine replacement therapy investigations have been limited to animalexperimentation until recently. Since the basic research had shownchanges resembling fibrocystic disease in women when iodine wasdeficient, the clinical analogy became apparent. The clinicalapplication of this basic research was started in 1969. Clinicaltreatment of women with fibrocystic disease was carried out usingLugol's solution (Strong Iodine Solution, U.S. Pat.), which is asolution containing 5% by weight iodine and 90% by weight potassiumiodide. Undesirable characteristics of Lugol'iodine are that it has avile taste and has the potential to disrupt thyroid function because ofthe presence of large quantities of sodium iodide. With the discovery ofiodine caseinate as a viable replacement for Lugol's ,solution, itbecame the basic treatment modality beginning in 1974.

This protein-bound iodine, Caseoiodine-lodaminol was administered indoses of 10 mg per day and resulted in an improvement rate of over 90%.These therapeutic trials by Ghent were enlarged in 1985 to 588Caseoiodine patients. The patients treated with iodine caseinateexperienced definite improvement both subjectively and objectively.Forty-three percent were symptom free and their breasts had returned tonormal. Fifty percent had residual premenstrual discomfort and fibroustissue collections on examination. (Caseoiodine has a small amount offree I₂ in its composition). In addition to the very favorable resultsobtained through the treatment of fibrocystic disease by iodinereplacement therapy, Ghent's patients did not have the massive sideeffects reported by Greenblatt in his treatment of mammary dysplasiawith danazol, as reported in Fertil, Steril 34, 1980.

Most recently (in August of 1984), clinical testing was begun by Ghentfor the treatment of fibrocystic dysplasia using an oral administrationof elemental iodine. As a result of treatment with aqueous iodine, 90%of patients treated have experienced dramatic reduction in breast sizecaused by cystic formation and reduction of the fibrosis and painassociated with this syndrome.

These clinical results parallel the laboratory results obtained in testsrun concurrently by Eskin in Philadelphia. Thin section photomicrographsof breast tissue from female rats show not only the control of cysts,including the abatement of epithelial hyperplasia but additionally, thecontrol and dissolution of the fibrous tissue characteristic offibrocystic disease. Heretofore, the complete reverse of fibrocysticdisease was not experienced using iodine replacement therapy. Onlytreatment with aqueous iodine resulted in the complete reversal of thefibrocystic dysplasia, including the control of fibrosis and thus areturn to normal.

FIG. 1 is a photomicrograph of the breast tissue of a human female. Thisphotomicrograph illustrates epithelial hyperplasia, cyst formation andincreased fibrous tissue associated with fibrocystic disease. Laboratorystudies on rats by Eskin allow for a comparative study of the relativeeffect of the various prior art iodine replacement therapy, includingsodium iodide, iodine caseinate, and elemental iodine as a treatment forfibrocystic disease, as illustrated by the other figures.

FIG. 2 is a photomicrograph of a normal female rat illustrating normalcellular configuration. The breast tissue includes a predominance ofadipose tissue with no exhibition of epithelial hyperplasia, cyst spacesor fibrous tissue.

In comparison, FIG. 3 illustrates rat breast tissue rendered iodinedeficient. The iodine deficient breast tissue shows cystic spaces,epithelial hyperplasia and increased fibrous tissue characteristic offibrocystic dysplasia. The comparison of FIGS. 2 and 3 support Eskin'sprevious findings relating iodine deficiency to fibrocystic diseasefirst reported in 1970 in the Annals New York Academy of SciencesJournal, Series II, Volume 32, 1970; 911-947 and updated in Iodine andBreast Cancer--A 1982 Update, Biological Trace Element Research, Volume5, 1983, 399-412. The material disclosed in these articles isincorporated herein by reference.

FIGS. 4 and 5 show the effect of estrogens on the breast tissue from afemale rat which was on an iodine deficient diet. FIG. 4 illustrates anenhancement of cystic spaces, marked increase in epithelial hyperplasiaand increased fibrosis between the secreting acini. This inconsistentwith the findings of Fratkin reported in the paper entitled "TheHyperoestrogen State" presented at North Pacific Surgery Meeting inTacoma, Wash. in 1980. A correlation was established between fibrocysticdysplasia and increased estrogen intake in milk drinkers. FIG. 5 isillustrative of the effect of estrogens when added to the breast tissuefrom a female rat which was on a normal iodine containing diet. Thecontrol rat shows some cyst formation and epithelial hyperplasia butwithout the fibrosis present in the tissue of the rat on the iodinedeficient diet.

The addition of the carcinogen, in this case dimethyl benzanthracene, tothe breast tissue from a female rat on an iodine deficient diet, resultsin the progression from the benign state of fibrocystic dysplasia toovert malignancy as seen in FIG. 6. This finding is supportive of theinventors' contention that fibrocystic disease enhances the risk ofbreast cancer causing sensitization of the breast tissue to variousstimuli, including carcinogens. This sensitization process may explainthe increased incidence of breast cancer in women in areas of deficientiodine intake, reported by Moosa et al. in "Thyroid Status and BreastCancer", Royal College of Surgeons, England, 53, 1975.

FIG. 7 illustrates the effect of sodium iodine as a replacementtreatment on breast tissue from a female rat which was on an iodinedeficient diet. The epithelial hyperplasia regressed and the cysticspaces disappeared, but the fibrous tissue remained. This is consistentwith the inventors' initial research on iodine replacement therapy forfibrocystic dysplasia beginning in 1969.

The effect of iodine caseinate on the morphology of rat breast tissue isillustrated in FIG. 8. This figure shows the subsidence of theepithelial hyperplasia and the reduction in cystic spaces, however thefibrosis remains unchanged.

In comparison, replacement treatment with elemental iodine is shown inFIG. 9. This figure shows a reversal of tissue morphology to near normalwith the return of normal adipose tissue components, subsidence of theepithelial hyperplasia and cyst spaces, and most notably, subsidence ofthe fibrosis (see also FIG. 2 for comparison). Heretofore, other formsof iodine replacement treatment of fibrocystic dysplasia have not beensuccessful in the control and reversal of fibrosis. This was clearly anunexpected result.

Parallel clinical testing by Ghent supports the laboratory findings ofEskin. Iodine replacement therapy with elemental iodine began in Augustof 1984. At that time, 142 women with fibrocystic disease were treatedwith aqueous iodine. Eighty of these women were patients who had been oniodine caseinate therapy for varying periods of time and had aresolution of the cystic component but with the continued existence offibrosis. The remainder of the sample group were patients who werestarted on aqueous iodine replacement therapy as the first form oftreatment.

Clinical observations of the 142 cases of fibrocystic dysplasiaindicated that both groups of patients had uniformly good results. Thefirst group still had some residual discomfort and some lumpiness fromthe fibrosis during their treatment with iodine caseinate. However, thepain was relieved in 90% of the patients in 4 to 16 months after beingswitched to aqueous iodine treatment. In addition, the patientsindicated that their breasts were softer and had reduced in size by 1/4to 2 cups in brassiere size. This is indicative of the reversal of thefibrosis.

The second group consisting of de novo patients, had similar dramaticresults in 4 to 16 months with control of pain, control of cysts, andcontrol of fibrosis. These patients also noted a decrease in breast sizeby 1/4 to 11/2 cups (brassiere size). This result was obtained in 90% ofthe patients treated.

The initial results of elemental iodine therapy were encouraging with aresolution of all the elements of the triad (see FIG. 9). These resultsinitiated further clinical testing on human volunteers suffering fromfibrocystic disease. Of these, two hundred fifty-three to date have hadsufficient follow-up to allow analysis.

It has been found that a daily dose of about 1.0 milligrams to about 20milligrams of elemental iodine (I₂), with a suitable pharmaceuticalcarrier, is effective in the treatment or prevention of iodinedeficiency diseases. A daily dosage of 2 to 12 milligrams of theelemental iodine has also been found to be effective in the treatment orprevention of iodine deficiency diseases. A daily dosage of about 3milligrams to about 6 milligrams of the elemental iodine has furtherbeen found to be effective for the treatment or prevention of iodinedeficiency diseases. The exact dosage can be selected depending upon thepatient's needs, as determined by the practicing physician.

Based on the body weight of the patient, it has been found that a dailydosage of 0.01 to 0.20 milligrams of elemental iodine, in a suitablepharmaceutical carrier, per kilogram body weight of the patient iseffective for the treatment or prevention of iodine deficiency diseases.It has further been found that a daily dosage of from about 0.03milligrams to about 0.16 milligrams of the elemental iodine per kilogramof body weight of the patient is effective for the treatment orprevention of iodine deficiency diseases. It has further been found thata daily dosage rate of about 0.07 milligrams to about 0.09 milligrams ofthe elemental iodine per kilogram body weight of the patient is alsoeffective for the treatment or prevention of iodine deficiency diseases.

In one example of the present invention, the elemental iodine can beadministered as an aqueous solution. The aqueous solution preferablycontains about 0.3 milligrams of elemental iodine per milliliter ofsolution.

In another example of the present invention, the elemental iodine can beadministered as a starch iodine complex, in tablet form, wherein eachtablet contains 3 milligrams of elemental iodine.

EXAMPLE 1 Elemental Iodine Therapy Study

The subjects of this study were volunteers who had been referred withnodular, painful, swollen breasts. The diagnosis of fibrocystic diseasewas made on clinical examination, thermography and mammography when theage of the patient permitted such diagnosis.

As shown in FIG. 12, the study group was divided into two sections. Thefirst group, the de novo group, numbered 108 and had not been treatedpreviously for fibrocystic disease. The second group, the transfergroup, numbered 145 and had been on iodine replacement therapy withcaseoiodine for a mean of thirty months but had experienced residualdiscomfort and fibrosis. The treatment of the transfer group wassuspended and all patients in the series received 3-6 mg of elementaliodine daily.

In establishing the dosage of aqueous iodine required to effectivelycontrol all symptoms associated with fibrocystic disease, Dr. Ghentestablished a dosage range of about 1.2 milligrams to about 6 milligramsper day of elemental iodine in aqueous solution with 3-6 milligrams perday being the most effective dose as noted above. These dosages werebased on a dosing rate of about 0.07 milligram to about 0.09 milligramof elemental iodine (I₂) per kilogram of the patient's body weight.

FIG. 10 shows the solubility of iodine in water and illustrates therelationship of iodine concentration as a function of temperature. Thissolubility curve was used to calculate the dosage range by Ghent and istaken from Black et al., "Use of Iodine For Disinfection" from Journalof American Waterworks Association, Volume 37, No. 11, November 1965.

Further, the half life of I₂ in the human appears to be eight hours andtherefore a daily dose is necessary. This is supported by clinicalevidence wherein 10 cases were reduced to a twice-weekly dose and withintwo weeks had a recurrence of symptoms. These clinical findings aresupported by the inventors' previous clinical testing wherein 89.5% ofpatients who stopped iodine replacement therapy had a recurrence ofsymptoms within a nine-month period.

The patients of the study group were reassessed at four months andsixteen months. As shown in FIGS. 13 and 14 the results of the studywere classified in four classes with Class 1 representing a subjectiveand objective return to normal. The patients of Class 2 had someresidual discomfort and some residual fibrosis. Classes 3 and 4 wereconsidered as poor results with continued pain, fibrosis and cysts.

The results in the de novo patients (FIG. 13) showed a completesubjective relief of breast pain and a clinical return to normal in 72%of patients with 26% retaining a small residual plaque of fibrosis atthe fourth month level. As objective confirmation of the patients'changed mammary status, 76% showed a reduction in breast size thatvaried from 1/4 to 2 cups in brassiere size.

The transfer group illustrated the most significant results with a lossof residual breast discomfort and a complete resolution of fibrosis in74% of the cases. A smaller percentage of patients (21%) were of Class 2experiencing minor cyclical pain and some remaining soft fibrosis (seeFIG. 4). It seems that the longer the duration of the fibrocysticsyndrome, the longer the time required for comfort and normalcy.Reduction in breast size was as significant as the de novo group (FIG.13).

A further group of patients were placed on a daily treatment ofelemental iodine wherein the elemental iodine was admixed with starch inthe form of a starch iodine complex wherein the iodine is present astriiodide ions (I₃ ⁻) or polyiodide ions (I₅ ⁻ up to I₁₁ ⁻). When thestarch iodine complex dissociates elemental iodine (I₂) is released andis the effective active ingredient. This form of pharmaceuticalformulation is described in detail in Applicants' copending applicationU.S. Ser. No. 08/272,308, filed Oct. 14, 1992 (continuation of U.S. Ser.No. 676,170, filed Mar. 28, 1991) and in published PCT ApplicationPCT/CA92/00115 (WO92/17190) published Oct. 15, 1992.

Examples of suitable dosages for the administration of the starch iodinecomplex are found below in Table 1.

                  TABLE 1                                                         ______________________________________                                                               Milligrams                                                                              Milligrams                                   Patient No.                                                                             Weight (kg)  I.sub.2 /Day                                                                            I.sub.2 /kg bw                               ______________________________________                                        1         81.82        6-9*      0.07-0.11                                    2         71.82        6         0.084                                        3         54.55        6         0.110                                        4         95.45        9         0.094                                        5         59.09        6         0.102                                        6         57.27        6         0.105                                        7         52.27        3         0.057                                        8         56.82        6         0.106                                        9         64.55        9         0.139                                        10        68.18        6         0.088                                        11        63.64        6         0.094                                        12        68.18        9         0.132                                        13        50.91        6         0.118                                        14        55.00        6         0.109                                        15        61.36        6         0.098                                                         Average =                                                                             0.103                                                ______________________________________                                         *Patient was started on 2 caps/day in Sept. 92 and switched to 3 caps/day     in Aug. 93.                                                              

EXAMPLE 2 Comparative Study of Caseoiodine Treatment

As noted above, Ghent and Eskin in 1985 enlarged their series ofcaseoiodine patents to 588 with an improvement rate of 93.4%. As shownin FIG. 11, this improvement rate was categorized originally in fourclasses, 1-4. The first group accounted for 43% of a subjective andobjective return to normal. The second group (50.4%) had some residualpremenstrual discomfort and had fibrosis that at best was only worrisomebut at worst could mask early malignant changes both clinically andmammographically.

A comparison of the results obtained with caseoiodine therapy and withelemental iodine therapy is revealing as shown in FIG. 14. Thecaseoiodine therapy resulted in the return to normal without pain in5.4% of patients (class 1), while 85.8% of patients experienced someresidual premenstrual pain and fibrosis (class 2). The results after thepatients were transferred to elemental iodine therapy were significantwith 73.7% of patients returning to complete normalcy (class 1) and21.3% again experiencing residual premenstrual pain and some fibrosis(class 2) at four months evaluation. This increased to over 90% at the16-month evaluation.

The various complications of iodine replacement therapy are listed inFIG. 15. These include acne, nausea, diarrhea, hair thinning, hyper- andhypothyroidism, skin rash and iodism. An increase of pain was alsoexperienced by patients: 18.5% of the de novo group and 1.3% of thetransfer group during the treatment cycle. This pain occurred three tosix weeks into the treatment regime and lasted from one to three weeks.The manifestation of pain seemed to coincide with a decrease in breastsize and a sudden softening of the fibrosis. Once this pain had subsidedit did not recur.

Based on the two series of clinical patients and in consideration of thevarious complications above, elemental iodine replacement therapy hasbeen found to be an effective treatment regime, more effective thanother forms of iodine replacement therapy, including treatment usingcaseoiodine. Iodine replacement therapy generally should be consideredbefore mastectomy, hormonal manipulation or neglect.

B. Iodine As Treatment and Prophylaxis for Breast Cancer

The present invention further provides a method and composition for thetreatment and prophylaxis of breast cancer. Particularly, elementaliodine interacts with breast estrogen receptors to reduce the prevalenceof breast cancer in susceptible animals and halt neoplastic changes inanimals with malignant breast cancer. Published clinical studies whichinclude those of the inventors, have shown evidence of iodine metabolismwithin the ducts and particularly in the terminal ducts (acini) of thebreast (Eskin, BA, Iodine Metabolism and Breast Cancer, Trans NY AcadSciences, 32: 911, 1970; Strum, JM, et al., "Resting Human Female BreastTissue Produces Iodinate Protein", J. Ultrastructure Res, 84: 130,1983). The infrastructures of breast secretory cells have been shown toboth organify iodides and to produce tyrosine/iodine compounds.

One prominent facet obtained from this research with iodine is theeffect of iodine deficient conditions on rat mammary glands. Thisdeficiency can be obtained either through the use of an iodine deficientdiet and/or through perchlorate treatment. Iodine deficient, buteuthyroid, rats exhibit mammary gland abnormalities which pass throughtransitional histological steps and resemble the fibrocystic,adenomatous, and fibrotic diseases present in women. In both rats andwomen these conditions are benign. Thus, the rat mammary gland serves asan excellent animal model for breast diseases.

Iodine deficiency causes a functional increase in breast estrogenreceptor activities, which disappears upon iodine replacement.Intracellular biochemical pathways appear to be responsible for thisresult. The biochemical pathway seems to be an intracellular attractionby iodine for estrogen receptors. The pathway also calls for thepresence of a small, intermediate protein which has been shown tofunction in active breast cells in combination with the iodine/tyrosineproducts. Thus, cell metabolism is altered when there is "inadequate"iodine present.

Iodides can be oxidized to iodine in the thyroid without difficulty.However, in the breast the peroxidase necessary for this transition maybe lacking or inactivated (DeSombre, E. R., et al., "Identifications,Subcellular Localizations and E₂ Regulation of Peroxidase" CancerResearch, 35: 172, 1975). Further basic research in this directionindicates that a unique iodine treatment for the breast has thecapability of providing normal intracellular responses.

Several iodinated compounds and chemical forms of iodine, such ascaseoiodine, sodium iodide (NaI) and potassium iodide (KI) have beentried for treating the resulting histopathologies from iodine deficiencyover the past ten years with only minimal success. However, theinventors have found that when aqueous or diatomic iodine is used, thehistopathology in the breast becomes normal.

Trials were first performed on a rat model, and then on women for thisbenign condition. The results show that diatomic iodine should beconsidered efficacious for the treatment of the fibrocystic diseases ofthe breast (Eskin, B. A., et al., "Etiology of Mammary GlandPathophysiology Induced By Iodine Deficiency"Frontiers in Thyroidology(Eds: Madiero-Noto, G. and Gatan, E.), New York: Plenum, 1986, p. 1027;Ghent, W. R., et al., "Fibrocystic Breast Dysplasia: A DeficiencySyndrome", Clin Invest Med (Canada), 9: A66 (R406), 1986; Ghent, W. R.,et al., "Elemental Iodine Supplementation in Clinical Breast Dysplasia",Proc Am Asso Ca Res, 27: 189 (751), 1986)).

The therapeutic iodine studies in women were originated after basicresearch in the mammary glands of rats. Iodine in its elemental formshows early evidence of effectiveness against neoplasia in the mammaryglands.

The interaction between iodine and the breast is not simply conjecture.Morbidity and mortality incidences in iodine deficient regions of theworld have been shown to be above average for breast diseases (benignand malignant). Regions with adequate or excessive iodine levels havemuch lower incidences of breast diseases. Iodine deficient regions inthe United States and Canada (described by the World HealthOrganization) similarly show a much higher census of breast cancer.

Early studies conducted by the inventors have shown iodine deficiencyappears to cause an increase in carcinogenesis when a known breastcarcinogen is given to susceptible rats. In some studies, earlier onsetof cancer is seen and in others a greater number of breast tumor sitesand an increased size of tumor have been described. Early attempts atreplacement with available iodides were partially responsive but in mostcases they were actually totally ineffectual. This situation is similarto that seen when benign diseases were initially treated using a ratmodel.

Iodine seems to be a requirement for normal cellular growth andmetabolism in the breast. Breast tissues may be iodine deficient,although adequate iodides are present for thyroid or other tissue needs.However, the unique biochemical pathway found in the breast seems torespond best to replacement with diatomic (elemental) iodine (I₂).

The daily dosage with elemental iodine I₂ for treatment or prophylaxisof breast cancer in humans is the same as that for the treatment offibrocystic dysplasia, namely about 1.0 milligrams to about 12milligrams of elemental iodine in a pharmaceutical carrier. In oneexample of the present invention, a daily dose of about 3 milligrams toabout 6 milligrams of elemental iodine was provided administered as anaqueous solution containing about 0.3 milligrams of elemental iodine permilliliter of solution. These dosages are based on a dosage rate ofabout 0.01 milligrams to about 0.20 milligrams elemental iodine (I₂) perkilogram of patient body weight. The precise dosage will depend upon thepatient's needs, as determined by the practicing physician. In thetreatment of breast cancer, these daily doses will cause the subsidenceof neoplastic changes in breast tissue, and when used for theprophylaxis of breast cancer, these daily doses will reduce theprevalence and the volume of breast cancer.

IODINE TREATMENT OF BREAST CANCER EXAMPLE 3 Spontaneous Breast Cancersin Rats

Since several different iodide modalities were used for evaluationwithout success, a preliminary study using iodine (diatomic, elemental)was begun by the inventors. This study employed Sprague-Dawley ratsunder severely iodine deficient conditions. The latter was obtained byusing both dietary and perchlorate treatment together. While most of thehistopathology obtained in the control rat group was noted to have onlysevere breast dysplasia, approximately 9% had evidence of neoplasia withcytological aberrations consistent with malignant alterations. Whendiatomic iodine was administered at a dosage of 0.5 mg per 100 gm bodyweight (orally) to the experimental groups, the breasts were noted tohave improved and there was no evidence of persisting neoplastic changesin any of the rats.

EXAMPLE 4 Iodine Treatment of Induced Breast Tumors in Rats

DMBA, a carcinogen, causes mammary gland neoplasia in rats. If thesetumors contain breast peroxidase, they respond to iodine and estrogentreatment. However, as the tumors become less responsive to iodine(hormone independent), breast peroxidase is found to be lacking.

The use of perchlorate as a peroxidase-blocking agent increases thetumorigenesis and the effectiveness of iodide therapy. Preliminarystudies with diatomic iodine at a dosage of about 0.5 mg per 100 gm bodyweight (orally or intraperitoneally) have shown the tumors to be moreresponse to both diatomic iodine and estrogen.

In basic research studies, elemental iodine has been shown to benecessary for normal estrogen receptor function in rats. Acharacteristic of breast cancer is the change in response to estrogenand estrogen receptor variability.

EXAMPLE 5 Prophylaxis Against Breast Cancer with Iodine

The incidence of breast cancer in women who had been treated withelemental iodine is less than the incidence of breast cancer in womenwho had not been so treated. The incidence of breast cancer in womentreated with elemental iodine was compared with other published results,namely the results as published by the Ontario Cancer Research, andresults published by Spratt. These results are shown below:

Ontario Cancer Research--16.50×10⁻⁴ cancers per women year (From OntarioCancer Treatment and Research Foundation, 1987, Table II, page 184)Spratt's series--16.40×10⁻⁴ cancers per women year (Journal of SurgicalOncology, Vol. 41, page 42, 1989)

Ghent series--6.25×10⁻⁴ cancers per women year (Dr. Ghent's clinic,Kingston, Ontario)

Evidence for the diatomic iodine replacement thesis was obtained in aprophylactic treatment regime where simultaneous therapy with diatomiciodine as described in Example 3 above, was given to a limited number ofprepared rats. The mammary glands showed no neoplasia secondary to thislow iodine diet/perchlorate treatment. This preliminary study showedthat diatomic iodine appears to restrict or abolish neoplastic growthand development under extreme iodine deficient conditions, where asignificant level (9%) of neoplastic changes was predicted from theresults of Example 3.

DIMETHYLBENZANTHRACENE STUDIES

Further confirmation of these results were obtained from a further ratmodel study, wherein rats which were pretreated with elemental iodinehad a reduction of mean tumor volume as compared to the nontreatedcontrols, when both of these rats were challenged with a chemicalcarcinogen.

After adequate orientation of 48 hours, 80 Sprague-Dawley virgin femalerats (A.A.I., PA) of 100-124 grams and approximately 37 days old, weredivided randomly into eight groups each containing 10 rats. The animalswere identified according to their phase, group, and rat numbers. Theeight groups were labelled as Groups, IA1, IA2, IB1, IB2, IIA1, IIA2,IIB1, and IIB2. Each rat was weighed and marked for identification. Earidentification were as follows:

    ______________________________________                                        Group #                Rat #                                                  ______________________________________                                        Left Ear                   Right Ear                                          Upper hole-1  Upper clip-4 Upper-1 (4,7)                                      Middle hole-2 Middle clip-5                                                                              Middle-2 (5,8)                                     Lower hole-3  Lower clip-6 Lower-3 (6,9)                                      Two holes-7                No hole-10                                         None-8                                                                        ______________________________________                                    

The rats in each group were housed in large rat cages, allowing no morethan four rats per cage and 23 sq. inches floor space per rat.

Group I was initially fed a normal diet and provided with doubledistilled drinking water (Ionics and IWT). Group II was initially fed aRemington iodine-deficient diet (Teklad, Wi) during which they receiveddouble distilled drinking water.

At the end of fourteen days, and at 50-56 days old, groups I and II weredivided into groups A and B. Groups IA and IIA were treated with 15 mg7,12 Dimethylbenzanthracene (Eastman Kodak, N.Y.) dissolved in 1 mlsesame oil by gavage. Groups IB and IIB were given a sham feeding of 1ml of sesame oil at this time also. Only 10 rats a day were given thistreatment. For the first twelve hours after treatment, the rats werehoused in the fume hood and then taken to the Animal House where theywere placed in the same room as groups IB and IIB. The rats in groups IAand IIA continued to be fed a normal diet and iodine-deficient diet,respectively. Groups IB and IIB also continued to receive theirrespective diets.

The following phases received iodine replacement therapy at these times:

Phase 1--at time of initial feeding of Remington diet

Phase 2--at time of DMBA pulse

Phase 3--at 10 days after DMBA treatment

Groups IA1, IB1, IIA1, and IIB1 received 2.67 ml/1000 ml dilution of a0.3 mg/ml "mother" iodine concentrate for the rest of the experiment.The technique for making the iodine solution was as follows:

1) 14 gms. prilled iodine was placed in a membrane which was sealed.

2) Membrane was placed in 1000 ml of DDH₂₀ O in a brown coated bottle.This was used as a concentrate.

3) The water was heated to 60° C. for 2 hours as a heat starter. Ittakes 24 hours to arrive at Black's Solubility Curve. This has a heatmass constant. (Stabilizes at 0.3 mg/ml)

4) A second container was used to measure 2.67 ml of concentrate to 1000ml DD H₂ O. This dilution was then used as drinking water for theanimals.

The following was the amount of iodine given per day:

0.3 mg/ml×2.67 ml/1000 ml×25 ml/day=0.2 mg/day or 20 μg/day.

This daily dosage corresponds to the rats receiving 0.07-0.09 mg perkilogram body weight. The other groups continued to receive doubledistilled drinking water. Thus, the groups were arranged in thefollowing order:

    ______________________________________                                        Group                No. of rats                                              ______________________________________                                        I. Normal diet                                                                A1-DMBA, iodine therapy                                                                            10                                                       A2-DMBA, no iodine therapy                                                                         10                                                       B1-No DMBA, iodine therapy                                                                         10                                                       B2-No DMBA, no iodine therapy                                                                      10                                                       II. Iodine-deficient diet                                                     A1-DMBA, iodine therapy                                                                            10                                                       A2-DMBA, no iodine therapy                                                                         10                                                       B1-No DMBA, iodine therapy                                                                         10                                                       B2-No DMBA, no iodine therapy                                                                      10                                                                            80                                                       ______________________________________                                    

Starting on day one and continuing until 150 days past initial DMBAexposure, each rat was weighed once a week.

Every three weeks, vaginal smears were performed for 5 consecutive days.A report of the stage of estrous and any abnormalities were noted foreach rat.

Palpations of the breasts were performed twice a week for the first 30days after pulse DMBA was administered. The masses, if any, were drawn,measured by caliper, described as to consistency and freedom of motion,and all observations were recorded. After 30 days, the aboveobservations were taken (including framing of tumor if larger than 5 mm)every 2 days and recorded.

Statistical analysis were performed on the results to determine thefollowing:

A. Number of rats/group; onset and time of initial detection

B. Mammary cancers per rat at necropsy

C. Mean time to mammary cancer detection

D. Growth rate after detection as expressed as volume-doubling time whencancer reaches 1 cm³

At 150 days past initial pulse dose of DMBA, groups I and II underwentCO₂ euthanasia. Vena cava serum, breast tissue, and thyroid tissue werecollected from each rat, labelled, and analysis performed forhistological data. Random weighing of adrenals, ovaries, thyroids, andbreasts were employed and recorded. Cell and tissue changes under theinfluence of iodine were observed by light cytohistology to indicate thecharacteristics of breast neoplasias. The following characteristics werenoted:

A) Cellular hyperplasia

B) Ductal hypertrophy

C) Fibrosis

D) Secretion

Neoplasia description will require the following observations:

A) Mean time of onset of cancer detection

B) Rate of tumor formation

C) Growth rate of tumors (doubling time)

Excision-biopsies of breast tumors were surgically removed underanesthetic whenever the greatest diameter of the rat tumor was largerthan 2.5 cm, or when the appearance of the tumor resembled any stage ofnecrosis. If necessary, a second biopsy was taken during the chronicstudy, if the tumor exceeded the established maximal size, in order thatthe animal complete the time (150 days), which is part of theexperimental design. Euthanasia was carried out if animal discomfortseemed to be present at any time.

The excision-biopsies were done under anesthesia given I.P. Thisanesthetic consisted of:

2 ml Ketaset (100 mg/ml)

1 ml Rompon (20 mg/ml)

0.15 ml PromAce (10 mg/ml)

Dose: 0.1 ml mix/100 g B.W.

The tumor surgery was limited to the breast and did not extend beyondthe fascia. After removal, subcutaneous running absorbable sutures orskin clips were used to close the skin. Follow-up was done after surgeryuntil vital signs recover. The rat was isolated and re-examined untilthe skin clips were removed and the rat could resume its activities inthe original cage. When surgery appeared to be in excess of the protocolor post-op is poor, euthanasia was required.

The results of these studies are shown on Table 2. This table shows thetwo main groups, Group 1 and Group 2. Group 1, which was initially fed anormal diet, and Group 2 which was initially fed a Remington iodinedeficient diet. Within the two groups are four subgroups, phases 1, 2and 3, and a control. Phase 1 received iodine replacement therapy at thetime of the initial feeding of either the Remington diet or the normaldiet. Phase 2 received iodine replacement therapy at the time of DMBAtreatment. Phase 3 received iodine replacement therapy 10 days afterDMBA treatment. The controls did not receive any iodine replacementtherapy.

As demonstrated from the results, pretreating the rats with iodinereplacement therapy prior to DMBA treatment, reduced the mean tumorvolume in the DMBA treated rats. These results quite clearly demonstratethe prophylactic capability of elemental iodine to reduce the mean tumorvolume in DMBA challenged rats, thus confirming the clinical datacollected thus far that women who are treated with elemental iodine havea lower incidence of breast cancer.

The dose used for treatment is in a range chosen for benign disease(that is fibrocystic disease of the breast). Since the dose that mightprove toxic is 10 to 20 times this dose, modification to improve theresults can be made by adjusting the dose higher.

                                      TABLE 2                                     __________________________________________________________________________    Mean Tumor Volume*: DMBA Treated Rats                                                        Week 10                                                                            Week 12                                                                            Week 14                                                                            Week 16                                                                            Week 18                                                                            Week 20                                                                            Week 22                                                                            Exp.                        __________________________________________________________________________    GROUP I                                                                       Normal Diet-Iodine Phase I                                                                   15.191                                                                             53.565                                                                             67.739                                                                             97.979                                                                             136.405                                                                            155.904                                                                            214.962                                                                            320.524                     Normal Diet-Iodine Phase II                                                                  7.603                                                                              57.853                                                                             106.887                                                                            140.751                                                                            216.033                                                                            247.025                                                                            320.468                                                                            534.001                     Normal Diet-Iodine Phase III                                                                 6.686                                                                              24.079                                                                             75.421                                                                             90.319                                                                             127.529                                                                            184.717                                                                            319.229                                                                            392.61                      Normal Diet-Control                                                                          21.744                                                                             33.451                                                                             79.839                                                                             148.307                                                                            197.307                                                                            264.371                                                                            328.232                                                                            461.2                       GROUP II                                                                      ID Diet-Iodine Phase I                                                                       4.048                                                                              23.367                                                                             65.244                                                                             119.156                                                                            155.189                                                                            174.49                                                                             238.883                                                                            337.516                     ID Diet-Iodine Phase II                                                                      0.216                                                                              54.934                                                                             111.962                                                                            168.475                                                                            269.008                                                                            401.774                                                                            519.122                                                                            613.044                     ID Diet-Iodine Phase III                                                                     5.816                                                                              36.68                                                                              81.81                                                                              177.888                                                                            203.824                                                                            356.807                                                                            393.328                                                                            500.435                     ID Diet-Control                                                                              25.435                                                                             58.454                                                                             123.057                                                                            196.918                                                                            231.99                                                                             306.082                                                                            389.649                                                                            509.238                     __________________________________________________________________________     *Volumes were calculated using the formula 4/3 π ((L + W) ÷ 2)         All measurements were recorded in centimetres designating the greatest        diameter the length and its corresponding greatest orthogonal diameter it     width.                                                                   

C. Iodine Treatment of Endometriosis

The present invention provides a method and composition for thetreatment of endometriosis. Particularly, elemental iodine minimize theovarian function and estrogen production to control endometriosis andalleviate its symptoms.

Endometriosis is characterized by hormonally responsive endometrialtissue implants in extra-uterine sites. The etiology of endometriosis isthought to be the transplantation of uterine lining cells through thefallopian tubes, the lymph channels and/or the blood stream to theabdominal cavity. Another suggested theory is that the peritoneumundergoes metaplasia to produce endometrial cells without direct accessto cellular transplants. The transplanted or transformed islands ofendometrial tissue act in a similar fashion to the uterine cells, withswelling and then bleeding at the time of menstruation.

Current treatment modalities for endometriosis are directed at thenormal fluctuations of the estrogen/progesterone complex. Medicationsinclude birth control pills, masculinizing hormones such as danazol, orestrogen suppression drugs such as tamoxifen. In older age groups, totalabdominal hysterectomy is the only therapy that is effective. All of themedical therapies are anti-estrogen.

It was found that the therapeutic treatment of human patients with aneffective amount of elemental iodine (I₂) in a pharmaceutical carriercaused a subsidence of the nodularity of the patient's pelvicperitoneum. An effective dose of elemental iodine (I₂) to cause such asubsidence of nodularity is about 1 to 20 milligrams per day. A dailydosage of elemental iodine for the treatment of endometriosis of about 3milligrams to about 6 milligrams is also useful. The daily dosage can beadministered in an aqueous solution containing about 0.30 milligrams ofelemental iodine per milliliter of solution.

One example of the daily dosage is based on the administration of about0.01 to about 0.2 milligrams of elemental iodine per kilogram of patientbody weight per day.

EXAMPLE 6 Treatment of Endometriosis With Iodine

In the course of treating patients with diatomic iodine for fibrocysticbreast dysplasia (Example 1, above) three patients had a coincidentdramatic decrease in their cyclic lower abdominal pain. Two patients(ages 17 and 15), both with a diagnosis of endometriosis and bothtreated with birth control pills previously with little result, weretreated with diatomic iodine for 10 and 18 months, respectively. Bothhad a complete amelioration of their pain within one cycle of startingthe medication.

As a trial, the medication was stopped in these patients, and, withinone cycle, they had severe pain again, with increasing nodularity of thepelvic peritoneum on rectal examination. The subjective symptoms andphysical findings again improved within one cycle of restarting diatomiciodine.

The third patient (age 36), had proven endometriosis that responded todiatomic iodine therapy within two cycles, with complete relief ofpelvic pain and improvement in the pelvic nodularity on rectalexamination. Upon stopping her medication, she was asymptomatic for twocycles, and then her pain returned.

This series of patients has responded to diatomic iodine, and duringtheir trial therapy were not on any other medication. The mechanism ofaction of the diatomic iodine in control of endometriosis may be throughthe "reduction" of ovarian function and estrogen production, such asseems to be the case in the treatment of premenstrual syndrome.

D. Iodine Treatment of Premenstrual Syndrome

The present invention further relates to a method and composition forthe treatment of premenstrual syndrome. Particularly, elemental iodinenormalizes the ovarian function and estrogen production to alleviate thesymptoms of premenstrual syndrome.

Premenstrual syndrome is defined as the cyclic recurrence in the lutealphase of the menstrual cycle of a combination of distressing physical,psychological and/or behavioral changes, of sufficient severity toresult in deterioration of interpersonal relationship and/orinterference with normal activities. The symptoms of premenstrualsyndrome include breast pain, swelling and tenderness, lower abdominalbloating, constipation, increased appetite with cravings for salt orchocolate, fatigue, emotional lability with temper tantrums, anger orcrying, depression, anxiety with tension, irritability with tendency toseek confrontations, aversion to sexual relations, insomnia, confusionand/or violence.

Although premenstrual syndrome has been classified as a psychiatricinstability in the premenstrual phase, psychiatric counselling has notproven to be an effective treatment. Other treatment modalities includeprogesterone administration, tranquilizers and pain control medication,surgical removal of the ovaries and naloxone administration. However,these other treatment modalities are also ineffective.

It was found that an effective treatment of premenstrual syndrome inhuman patients entailed the administration of an effective amount ofelemental iodine (I₂). The dose of the elemental iodine had to besufficient to normalize the patient's ovarian function and estrogenproduction (both of which are abnormal in patient's with premenstrualsyndrome).

An effective amount of elemental iodine (I₂), in a pharmaceuticalcarrier, to normalize the ovarian function and estrogen production isabout 1.0 to about 12 milligrams per day. In one embodiment of theinvention, a daily dosage of about 3 milligrams to about 6 milligramsper day was found to be effective. These doses are based on a dailydosing range of about 0.01 to about 0.20 milligrams elemental iodine(I₂) per kilogram of patient body weight. In one example of theinvention, the daily dosage is administered as an aqueous solutioncontaining about 0.3 milligrams of elemental iodine per milliliter ofsolution.

EXAMPLE 7 Treatment of Premenstrual Syndrome With Iodine

Diatomic iodine has been used for the treatment of fibrocystic disease(see Example 1, above). During this treatment, ten women not only hadimprovement of their breast pain, but also volunteered that theirpremenstrual syndrome was controlled in part or totally. This wassignificant because premenstrual syndrome was not discussed at theirinitial consultation, but each woman, at her four-month evaluation,spontaneously reported amelioration of her premenstrual syndrome withintwo menstrual cycles of beginning treatment. These women varied in agefrom 30 years to 45 years, with an average of 38 years. The dose ofelemental iodine employed was from about 0.07 mg. to about 0.09 mg. perkilogram body weight per day.

In a retrospective review, the presence of their syndrome was confirmedby their family doctor, and all reported failure of control of thepremenstrual syndrome with various medications. All these patients metthe research diagnostic criteria for premenstrual syndrome as defined bySteiner, Haskett and Carroll. Five were classified as moderate, and fiveas severe. Subsequent follow up has shown continuation of control of thesyndrome. Three patients stopped their medication and within onemenstrual cycle had a return of symptoms.

E. Iodine Treatment of Ovarian Cysts

The present invention further relates to a method and composition forthe treatment of ovarian cysts. Particularly, the elemental iodinenormalizes the ovarian metabolism and estrogen response to preventand/or treat the occurrence of ovarian cysts.

As with the other medical indications, the action of diatomic iodine inpreventing or treating ovarian cysts is thought to be through abiochemical reduction of ovarian metabolism and estrogen response.

An effective amount of elemental iodine I₂, in a suitable pharmaceuticalcarrier to normalize the ovarian function and estrogen production isabout 1.0 to about 12 milligrams per day. In one embodiment of theinvention, a daily dosage of about 3 milligrams to about 6 milligramsper day was found to be effective. These doses are based on a dailydosing range of about 0.01 to about 0.20 milligrams elemental iodine(I₂) per kilogram of patient body weight. In one example of theinvention, the daily dosage is administered as an aqueous solution,containing about 0.3 milligrams of elemental iodine per milliliter ofsolution.

EXAMPLE 8 Treatment of Ovarian Cysts with Iodine

One patient, Number 647, exemplified four of the possible effective usesof elemental iodine, i.e., for the treatment of fibrocystic breastdisease, premenstrual syndrome, endometriosis, and ovarian cysts. Ineach situation, as previously described, the elemental iodine is actingas an anti-estrogen to normalize the ovarian metabolism and estrogenresponse.

A synopsis of the case follows. This patient had a previous rupturedfollicle cyst of the right ovary and was referred to the private clinicfor pelvic pain prior to her menarche. After menarche, the patient hadrecurrent episodes of right and left lower quadrant abdominal pain. Anultrasound of the pelvis, at the time of initial treatment withelemental iodine, revealed a cyst of the left ovary of approximately 1cm in diameter. After approximately 3 months on elemental iodine, thepatient was free of abdominal pain. The patient stopped taking theelemental iodine for 1 week and found that on the eighth day, herabdominal pain returned, severe enough to incapacitate her. Sherestarted the iodine and within 10 days the abdominal pain had subsided.A repeat ultrasound done approximately 10 months after initial treatmentof iodine revealed that the cyst on her left ovary had disappeared.Approximately six months later, this patient was also diagnosed withendometriosis (presence of chocolate cysts) during a laparoscopyexamination.

After a period of no abdominal pain, the patient stopped taking theelemental iodine for a period of approximately 2 years. She thenreturned to the private clinic, again having abdominal pain, and inaddition, breast pain. She was at that time diagnosed as havingfibrocystic disease in the upper half of each breast. The elementaliodine was again prescribed for her fibrocystic disease, and to continueto control her endometriosis disease, which was diagnosed on her initiallaparoscopy exam. An ultrasound done approximately 6 months afterelemental iodine retreatment showed the ovaries to be normal.

The patient continued on the elemental iodine, but was given an oralcontraceptive as well. The patient 1 year later reported that she wasfree of abdominal pain. However, she stated that if she stopped theiodine medication, she developed recurrent abdominal pain within threemonths presumably because of ovarian cysts.

Approximately 2 years after re-treatment with elemental iodine herbreasts were asymptomatic and normal on examination. She was alsoasymptomatic in regard to her abdomen. The patient at all times wastreated with 10 ml of an aqueous solution elemental iodine, twice daily,corresponding to a dose of approximately 6 milligrams per day.

While the present invention has been described in connection withspecific embodiments thereof, it will be understood that it is capableof further modifications. This disclosure of the invention is intendedto cover any variations, uses or adaptations of the invention followingin general, the principles of the invention, and including suchdepartures from the present disclosure as come within known andcustomary practice within the art to which the invention pertains.

We claim:
 1. A method for therapeutically treating or preventing aniodine deficiency disease or disorder selected from the group consistingof fibrocystic dysplasia, breast cancer, endometriosis, ovarian cystsand premenstrual syndrome, comprising administering to a mammal in needthereof a sufficient amount of elemental iodine.
 2. The method of claim1 wherein the amount of elemental iodine that is administered from about0.01 to about 0.20 milligrams of elemental iodine per kilogram bodyweight per day.
 3. The method of claim 2 wherein the amount of elementaliodine that is administered from about 0.03 to about 0.16 milligrams ofelemental iodine per kilogram body weight per day.
 4. The method ofclaim 1 wherein the elemental iodine is administered at a dose of fromabout 1 to about 20 milligrams per day.
 5. The method of claim 4 whereinthe elemental iodine is administered at a dose from about 2 to about 12milligrams per day.
 6. The method of claim 2, wherein elemental iodineis administered from about 0.01 to about 0.20 milligrams per kilogrambody weight per day for treating fibrocystic dysplasia.
 7. The method ofclaim 2, wherein elemental iodine is administered from about 0.01 toabout 0.20 milligrams per kilogram body weight per day for treatingbreast cancer.
 8. The method of claim 2, wherein elemental iodine isadministered from about 0.01 to about 0.20 milligrams per kilogram bodyweight per day for preventing breast cancer.
 9. The method of claim 2,wherein elemental iodine is administered from about 0.01 to about 0.20milligrams per kilogram body weight per day for treating endometriosis.10. The method of claim 2, wherein elemental iodine is administered fromabout 0.01 to about 0.20 milligrams per kilogram body weight per day fortreating ovarian cysts.
 11. The method of claim 2, wherein elementaliodine is administered from about 0.01 to about 0.20 milligrams perkilogram body weight per day for treating premenstrual syndrome.